Head and neck squamous cell cancer (HNSCC) is characterized by "field cancerization", precancerous changes in the upper aerodigestive tract mucosa cells that are believed to cause multiple primary tumors in the same patient. Second primary tumors are the chief cause of treatment failure in cancer patients. Ethanol has been shown to be dramatically synergistic with tobacco in HNSCC carcinogenesis. While ethanol or tobacco, alone, can each increase the risk of developing HNSCC 2 to 6 fold, this risk increases up to 50-fold with consumption of both ethanol and tobacco. We hypothesize that ethanol creates a selective advantage for transformed cells over normal cells. Tobacco carcinogens can transform oral mucosa cells and cause loss of sensitivity to apoptosis signals. Long-term exposure to ethanol has been shown to cause apoptosis of normal oral mucosa cells. Over time, exposure of oral mucosa cells to ethanol can lead to a net loss of normal cells relative to transformed cells. This model of recurrent apoptosis of normal cells with selection for apoptosis-resistant cells can account for the synergistic effect of ethanol and tobacco as well as field cancerization. We propose to test this model with the aim of developing novel chemoprevention strategies for HNSCC.